SETD2 histone modifier loss in aggressive GI stromal tumours.

Area of Science:

• Oncology
• Genetics
• Epigenetics

Background:

• Gastrointestinal stromal tumors (GISTs) exhibit variable clinical aggressiveness.
• Identifying genetic drivers of high-risk GIST is crucial for prognostic assessment.

Purpose of the Study:

• To identify genetic alterations linked to high-risk GIST.
• To explore the molecular and functional consequences of these alterations.
• To evaluate their utility as prognostic markers for GIST.

Main Methods:

• Exome sequencing of 18 GISTs (high-risk/metastatic and low/intermediate-risk).
• Prevalence screening of candidate alterations in an independent cohort (n=120).
• Functional assays (SETD2 mutation impact on H3K36me3, DNA damage, transcriptomics, and DNA methylation).

Main Results:

• High-risk GISTs have significantly more somatic mutations than low-risk GISTs.
• SETD2 mutations were found in 11.2% of high-risk GISTs but none of the low-risk GISTs.
• SETD2 mutations correlated with decreased H3K36me3, increased DNA damage, HOXC gene overexpression, and hypomethylated heterochromatin, all associated with shorter relapse-free survival.

Conclusions:

• SETD2 functions as a novel GIST tumor suppressor gene.
• SETD2 genetic status and associated epigenomic changes can inform GIST risk stratification.
• These findings offer insights into the mechanisms driving GIST clinical aggressiveness.